Novel combinations of a h3 antagonist and a noradrenaline reuptake inhibitor, and the therapeutical uses thereof

ABSTRACT

The present invention relates to combinations of a H3 antagonist and an antidepressant, which exhibit a synergistic wake promoting activity.

The present invention concerns novel combinations and their uses fortreating wakefulness disorders in patients suffering from deficientnoradrenaline release.

Wakefulness is controlled by several monoaminergic neuronal systems inbrain, mainly the histaminergic and noradrenergic systems which areactive during wake and silent during sleep. Hence, increase in histamineor noradrenaline release results in wake promotion at the expense ofsleep states.

Histamine H3 receptor antagonist/inverse agonists (X. Ligneau et al. J.Pharmacol. Exp Ther. 2007, 320, 365, J. S. Lin et al. Neurobiology ofDisease 2008, 30, 74, R X Guo et al. Brit. J. Pharmacol. 2009, 157, 104)are known to modulate sleep/wake increasing wakefulness.

WO 2006/117609 discloses H3 ligands such as(3S)-4-{4-[3-(3-methylpiperidin-1-yl)propoxy]phenyl}pyridine 1-oxide offormula:

herein referred as “compound (A)”, and their pharmaceutically acceptablesalts, hydrates, or hydrated salts.

Pitolisant (Wakix®) (ie) the monohydrochloride salt of1-{3-[3-(4-chlorophenyl)propoxy]propyl}piperidine has been one of thefirst H3 antagonists/inverse agonists on the market and is currentlyauthorized in Europe for the treatment of narcolepsy with or withoutcataplexy.

The effect of H3 antagonists on noradrenaline has been disclosed in A DMedhurst et al. (J. Pharmacol. Exp. Ther. 2007, 321, 1032-1045), G. Fliket al. (J. Mol. Neurosci. 2015, 56, 320-328) and J. S. Lin et al.(Neurobiology of Disease 2008, 30, 74-83). Antidepressants withnoradrenaline reuptake inhibitor properties such as duloxetine,reboxetine, atomoxetine, venlafaxine . . . . (C. Sanchez et al.Pharmacol. Biochem. Behay. 2007, 86, 468) increase wake at the expenseof deep sleep and/or REM sleep.

Kallweit ET AL (EXPERT OPINION ON PHARMACOTHERAPY vol. 18, no. 8, 2017,pages 809-817) reports the pharmacological management of narcolepsy withdepression, and suggests e.g. venlafaxine.

Lin E T AL (Neurobiology of Disease, vol. 30, no. 1, 2008, pages 74-83)discloses the use of tiprolisant combined with modafinil.

It has now been discovered that the combination of a H3 antagonist withan antidepressant chosen from the noradrenaline reuptake inhibitors,unexpectedly leads to tremendous increase in the quiet wake and decreasein the REM sleep, which are respectively enhanced/diminished in asupra-additive, synergistic manner as compared to the effect of eachcompound given alone.

According to a first object, the present invention thus concerns acombination of:

-   -   a H3 antagonist or inverse agonist of formula:

-   -   Where in formula (I):    -   R¹ is H or Methyl,    -   R² is Cl or

-   -    where * represents the position of attachment to the phenyl        ring,    -   n is 0 or 1,    -   and    -   an antidepressant chosen from the noradrenaline reuptake        inhibitors.

According to an embodiment, said H3 antagonist/inverse agonist is chosenfrom one of the following compounds:

And any of their pharmaceutically acceptable salts, or solvates thereof.

More particularly, said H3 antagonist/inverse agonist is thehydrochloride salt of

More particularly said H3 antagonist/inverse agonist is thedihydrochloride, tetrahydrate of

(herein called BP1.3656B).

According to an embodiment, the compounds may be in the form of theirfree base, or alternatively, in the form of pharmaceutically acceptablesalts such as hydrochloride, oxalate, dihydrochloride, hydrobromide,dihydrobromide, naphthalene-1,5-disulfonate, sulfate,ethane-1,2-disulfonate, cyclamate, toluenesulfonate,paratoluenesulfonate, thiocyanate, nitrate, methanesulfonate,dodecylsulfate, naphthalene-2-sulfonate, benzenesulfonate,dichloroacetate, glycerophosphate, 2-hydroxyethanesulfonate, aspartate,maleate, phosphate, ethanesulfonate, camphor-10-sulfonate, glutamate,alginate, pamoate, 2-oxo-glutarate, 1-hydroxy-2-naphthoate, malonate,gentisate, salicylate, tartrate, fumarate, galactarate, citrate,glucuronate, lactobionate, 4-aminosalicylate, glycolate,sesquiglycolate, glucoheptonate, pyroglutamate, mandelate, malate,hippurate, formate, gluconate, lactate, oleate, ascorbate, benzoate,succinate, 4-acetamidobenzoate, glutarate, cinnamate, adipate, sebacate,camphorate, acetate, caproate, nicotinate, isobutyrate, propionate,caprate caprylate, caproate, laurate, palmitate, stearate,undecen-10-oate, caprylate, orotate, carbonate, 5-sulfocalicylate,1-hydroxy-2-naphtoate, 3-hydroxy-2-naphtoate; and/or solvates such ashydrates, ethanolate, hemiethanolate.

Accordingly, the expression “compound” as used herein also refers to thepharmaceutically acceptable salts thereof and/or the solvates of saidunless specified otherwise.

According to an embodiment, the antidepressant is chosen from fromduloxetine, reboxetine, atomoxetine, desipramine, venlafaxine,desvenlafaxine, more particularly duloxetine. According to anembodiment, said antidepressant is not venlafaxine. According to anembodiment, said antidepressant is a noradrenaline reuptake inhibitorchosen from duloxetine, reboxetine, atomoxetine, desipramine,desvenlafaxine, in particular duloxetine, reboxetine, atomoxetine,desipramine.

According to an embodiment,

-   -   said H3 antagonist/inverse agonist is chosen from one of the        following compounds:

-   -   and any of their pharmaceutically acceptable salts, or solvates;        and    -   said noradrenaline reuptake inhibitor is chosen from duloxetine,        reboxetine, and atomoxetine.

According to an embodiment, the combination is the combination of

HCl (pitolisant) with duloxetine.

According to another object, the present invention also concerns apharmaceutical composition comprising a combination according to theinvention, wherein both ingredients are administered simultaneously,separately, or staggered over time.

According to another object, the present invention also concerns thecombination of the invention for use for treating and/or preventing adisorder chosen from excessive daytime sleepiness, substance such asalcohol abuse disorders, and/or with attention and cognitive deficit, ina patient suffering from deficient noradrenaline release.

The identification of those subjects who are in need of treatment ofherein-described diseases and conditions is well within the ability andknowledge of one skilled in the art. A clinician skilled in the art canreadily identify, by the use of clinical tests, physical examination,genetic tests and medical/family history, those subjects who are in needof such treatment.

According to an embodiment, said disorder is excessive daytimesleepiness and occurs in a patient suffering from:

-   -   Narcolepsy with and without cataplexy,    -   Idiopathic hypersomnia,    -   Daytime sleepiness disorders,    -   Obstructive sleep apnea,    -   Circadian rhythm sleep-wake disorders,    -   Parkinson's disease, or    -   Prader-Willi Syndrome.

According to an alternative embodiment, said disorder is attention andcognitive deficit and occurs in a patient suffering from attentiondeficit and hyperactivity disorder (ADHD).

According to a further alternative embodiment, said disorder isexcessive daytime sleepiness, attention and cognitive deficit and occursin a patient suffering from depression.

According to a still further alternative embodiment, said disorder ischosen from substance abuse withdrawal syndromes.

It should be noted that the alternative embodiment are not mutuallyexclusive and may be considered in addition to each other.

Actual dosage levels of the compounds may be varied so as to obtain anamount of active ingredient that is effective to obtain a desiredtherapeutic response for a particular composition and method ofadministration. The selected dosage level therefore depends upon thedesired therapeutic effect, on the route of administration, on thedesired duration of treatment and other factors, e.g. the condition ofthe patient.

A therapeutically effective amount can be readily determined by theattending diagnostician, as one skilled in the art, by the use ofconventional techniques and by observing results obtained underanalogous circumstances. In determining the therapeutically effectiveamount, a number of factors are considered by the attendingdiagnostician, including, but not limited to: the species of subject;its size, age, and general health; the specific disease involved; thedegree of involvement or the severity of the disease; the response ofthe individual subject; the particular compound administered; the modeof administration; the bioavailability characteristic of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The amount of the compounds which is required to achieve the desiredbiological effect will vary depending upon a number of factors,including the type of formulation of the drug to be administered, thetype of disease, the disease state of the patient and the route ofadministration.

In general terms, the preferred dosage of a drug to be administered islikely to depend on such variables as the type and extent of progressionof the disease or disorder, the overall health status of the particularpatient, the relative biological efficacy of the compound selected, andformulation of the compound excipient, and its route of administration.

The daily dose of the H3 antagonist/inverse agonist (I) may generally becomprised between 1 μg and 50 mg a day per patient. As an illustration,the preferred doses for pitolisant are 5-40 mg/day, more preferably10-30 mg/day, and for BP1.3656B 1-100 μg/day, preferably 5-30 μg/day

The daily dose of the antidepressant may generally be comprised between2 mg and 250 mg a day per patient. Illustrated doses are detailed below:

Desipramine: 10-300 mg/day, preferably 25-200 mg/day; Duloxetine: 20-120mg/day, preferably 30-60 mg/day; Venlafaxine: 35-375 mg/day, preferably35-225 mg/day; Desvenlafaxine: 50-400 mg/day, preferably 50-100 mg/day;Atomoxetine: 10-100 mg/day, preferably 10-60 mg/day; Reboxetine: 2-12mg/day, preferably 2-8 mg/day.

According to a further embodiment, the method of the invention alsocomprises the administration of one or more further active ingredient,selected from anti-Parkinson drugs such as levodopa, ropinirole,lisuride, bromocriptine, pramixepole or selected from anti-narcolepticor purported anti-narcoleptic drugs from another class includingmodafinil.

The compounds can be formulated into the same or distinct pharmaceuticalcompositions by admixture with one or more pharmaceutically acceptableexcipients.

The compositions may conveniently be administered in unit dosage formand may be prepared by any of the methods well known in thepharmaceutical art, for example, as described in Remington: The Scienceand Practice of Pharmacy, 20^(th) ed.; Gennaro, A. R., Ed.; LippincottWilliams & Wilkins: Philadelphia, Pa., 2000.

The compounds may be administered by various administration routes suchas oral; parenteral including sub-cutaneous, intramuscular,intra-venous; sublingual, topical; local; intratracheal; intranasal;transdermal or rectal, the active ingredients being combined with apharmaceutically acceptable excipient or vehicle in one or twopharmaceutical compositions.

In particular, the formulations suitable for parenteral administrationare sterile and include emulsions, suspensions, aqueous and non-aqueousinjection solutions, which may contain suspending agents and thickeningagents and anti-oxidants, buffers, bacteriostats and solutes whichrender the formulation isotonic, and have a suitably adjusted pH, withthe blood of the intended recipient. For the topical application, thecompositions of the invention may be used as creams, gels, ointments orlotions.

According to the invention, oral administration of the compound (I) orcomposition in an appropriate formulation is advantageously used.Formulations which are suitable to be administered orally to a patientinclude discrete units such as capsules, such as soft or hard gelatine,tablets, each containing a predetermined amount of the compound offormula (I). They also include powder; granules; solutions orsuspensions in an aqueous liquid or a non-aqueous liquid, oroil-in-water liquid emulsion or water-in-oil liquid emulsion.Gastrointestinal resistant formulations are also contemplated for oralformulations, in particular for duloxetine.

“Pharmaceutically” or “pharmaceutically acceptable” refer to molecularentities and compositions that do not produce an adverse, allergic orother untoward reaction when administered to an animal, or a human, asappropriate.

As used herein, “pharmaceutically acceptable excipient, vehicle orcarrier” includes in particular diluents, adjuvants, excipients, orvehicles. The use of such ingredients for pharmaceutical activesubstances is well known in the art.

In the context of the invention, the term “treating” or “treatment”, asused herein, means reversing, alleviating, inhibiting the progress of,or preventing the disorder or condition to which such term applies, orone or more symptoms of such disorder or condition.

“Therapeutically effective amount” means an amount of acompound/medicament according to the present invention effective inproducing the desired therapeutic effect.

According to the invention, the term “patient”, or “patient in needthereof”, is intended for a human or non-human mammal affected or likelyto be affected with the above disorders. Preferably, the patient is ahuman.

The compounds may be administered in unit dosage forms, wherein the term“unit dose” means a single dose which is capable of being administeredto a patient, and which can be readily handled and packaged, remainingas a physically and chemically stable unit dose comprising either theactive compound itself, or as one or two pharmaceutically acceptablecompositions.

The appropriate unitary dosage forms comprise the oral forms; thesublingual, buccal, intratracheal, intraocular, intranasal forms, byinhalation, the topical, transdermal, sub-cutaneous, intramuscular orintra-venous, and the rectal forms and the implants.

FIGURES

FIG. 1 represents the drug-induced changes in sleep-wake balance over 12hours post dosing in rats (Mean±SEM of 15 to 16 individual values) inquiet wake duration (FIG. 1A) and REM sleep duration (FIG. 1B) followingadministration of pitolisant and duloxetine

FIG. 2 represents the drug-induced changes in sleep-wake balance over 12hours post dosing in rats (Mean±SEM of 15 to 16 individual values) inquiet wake duration (FIG. 2A) and REM sleep duration (FIG. 2B) followingadministration of compound BP1.3656B and duloxetine.

FIG. 3 represents the drug-induced changes in sleep-wake balance over 12hours post dosing in rats (Mean±SEM of 15 to 16 individual values) inquiet wake duration (FIG. 3A) and REM sleep duration (FIG. 3B) followingadministration of pitolisant and reboxetine.

FIG. 4 represents the drug-induced changes in sleep-wake balance over 12hours post dosing in rats (Mean±SEM of 15 to 16 individual values) inquiet wake duration (FIG. 4A) and REM sleep duration (FIG. 4B) followingadministration of pitolisant and atomoxetine.

FIG. 5 represents the drug-induced increase in noradrenaline release inrat prefrontal cortex over basal release (AUC over 150 min post dosing)following administration of pitolisant and duloxetine (Mean±SEM of 6 to9 individual values).

EXAMPLES Example 1: Effect on Sleep/Wake

Effects on sleep/wake parameters were investigated in male Wistar rats.Briefly, rats were stereotaxically implanted with cortical electrodesfor electroencephalogram (EEG) recording using a telemetric system (DataSciences Int., Saint Paul, Minn., USA) for the acquisition, transfer andstorage of motor activity and EEG signals. EEG signals were analysedaccording to a procedure adapted from the algorithm proposed by R. P.Louis et al. (J. Neurosci. Methods, 2004, 133, 71-80) and the analysisof vigilance stages according to H. Kleinlogel (Neuropsychobiol.1990-91, 23, 197-204) after a fast Fourier transformation of 8-secondduration EEG epochs. This allows the determination for each epoch of itsvigilance stage (i.e. active wakefulness, quiet wakefulness, light ordeep slow wave sleeps and REM sleep also named paradoxical sleep). Ratsreceived orally (gavage) vehicle, drug or drug combination around 30minutes before the light onset. Then, EEG signals were continuouslyrecorded and further integrated over the 12-hour diurnal phase.

Effects on sleep/wake recorded in rats of drugs alone or combined arepresented in the FIG. 1 (Pitolisant/duloxetine), FIG. 2(BP1.3656B/duloxetine), FIG. 3 (pitolisant/reboxetine) and FIG. 4(pitolisant/atomoxetine):

In the case of the pitolisant/duloxetine combination, the combinationwas shown to lead to an increase in the quite wake of +35% as comparedto a cumulated increase of +19%. In addition, when the two compounds arecombined, the decrease in the REM sleep elicited by duloxetine ispotentiated compared to the effect of duloxetine alone (−35% vs.−23%)whereas pitolisant itself over 12 hours does not have any significanteffect.

Example 2: Noradrenaline Release in the Prefrontal Cortex

Both histamine H3 receptor antagonist/inverse agonists (J. S. Lin et al.Neurobiology of Disease 2008, 30, 74, G. Flik et al. J. Mol. Neurosci.2015, 56, 320) and noradrenaline reuptake inhibitors (F. P. Bymaster etal. Current Pharmaceutical Design, 2005, 11, 1475, F. P. Bymaster et al.Neuropsychopharmacol. 2002, 27, 699) are known to enhance theextracellular noradrenaline in the prefrontal cortex and reflecting anactivation of the noradrenergic neurotransmission. However, in bothcases, the enhancement is limited.

Effects on noradrenaline release in the prefrontal cortex wereinvestigated in vivo by microdialysis in vigil male Wistar rats asdescribed by AD Medhurst et al. (J. Pharmacol. Exp. Ther. 2007, 321,1032-1045) and G. Flik et al. (J. Mol. Neurosci. 2015, 56, 320-328).Briefly, anaesthetized rats were implanted with a guide cannulae forsampling in the prefrontal cortex. After at least one week of recoverypost-surgery, the microdialysis probe was inserted in the guide cannulaeand perfused continuously with artificial cerebrospinal fluid (CSF). Therat was habituated to the microdialysis cage for −3 hours. Then, ratsreceived orally (gavage) vehicle, drug or drug combination. CSF samplescollected every 30 minutes were analysed for their noradrenaline contentby HPLC coupled to a electrochemical detection. Noradrenaline samplelevels were expressed in percentage of basal noradrenaline releaserecorded over 1.5 hour before vehicle or drug treatment.

Unexpectedly, when the two types of compounds are combined, theactivation of the noradrenergic neurotransmission in the prefrontalcortex is enhanced in a synergistic manner as shown by the followingdata and illustrated in FIG. 5:

Maximal increase recorded over 150 min post dosing Maximal increase (%of statistics p value versus drug basal noradrenaline release) salinepitolisant duloxetine pitolisant +148 ± 49% >0.05 duloxetine +113 ± 31%<0.05 combination  +385 ± 115% <0.05 <0.05 <0.05

Hence, the association of the two classes of compounds may allow adecrease in the dosage of each component and, thereby, enhancedtolerance.

1. A combination of: a H3 antagonist or inverse agonist of formula:

Where in formula (I): R¹ is H or Methyl, R² is Cl or

 where * represents the position of attachment to the phenyl ring, n is0 or 1, and an antidepressant chosen from the noradrenaline reuptakeinhibitors.
 2. The combination according to claim 1 wherein saidantidepressant is not venlafaxine.
 3. The combination according to claim1 wherein said antidepressant is a noradrenaline reuptake inhibitorchosen from duloxetine, reboxetine, atomoxetine, desipramine,desvenlafaxine.
 4. The combination according to claim 1, wherein said H3antagonist/inverse agonist is chosen from one of the followingcompounds:

And any of their pharmaceutically acceptable salts, or solvates thereof.5. The combination according to claim 1, wherein said H3antagonist/inverse agonist is the hydrochloride salt of


6. The combination according to claim 1, wherein said noradrenalinereuptake inhibitors are chosen from duloxetine, reboxetine, atomoxetine,desipramine.
 7. The combination according to claim 1, wherein: said H3antagonist/inverse agonist is chosen from one of the followingcompounds:

and any of their pharmaceutically acceptable salts, or solvates; andsaid noradrenaline reuptake inhibitor is chosen from duloxetine,reboxetine, and atomoxetine.
 8. The combination according to claim 1which is the combination of

or a pharmaceutically acceptable salt thereof, with duloxetine.
 9. Thecombination according to claim 1 which is the combination of

or a pharmaceutically acceptable salt thereof, with duloxetine.
 10. Apharmaceutical composition comprising a combination according to claim1, wherein both ingredients are administered simultaneously, separately,or staggered over time.
 11. A method for treating and/or preventing adisorder chosen from excessive daytime sleepiness, substance such asalcohol abuse disorders, and/or with attention and cognitive deficit, ina patient suffering from deficient noradrenaline release, comprisingapplying an effective amount of the combination of claim
 1. 12. Themethod according to claim 11, wherein said disorder is excessive daytimesleepiness and occurs in a patient suffering from: Narcolepsy with andwithout cataplexy, Idiopathic hypersomnia, Daytime sleepiness disorders,Obstructive sleep apnea, Circadian rhythm sleep-wake disorders,Parkinson's disease, or Prader-Willi Syndrome.
 13. The method accordingto claim 11 wherein said disorder is attention and cognitive deficit andoccurs in a patient suffering from attention deficit and hyperactivitydisorder (ADHD).
 14. The method according to claim 11 wherein saiddisorder is excessive daytime sleepiness, attention and cognitivedeficit and occurs in a patient suffering from depression.
 15. Themethod according to claim 11 wherein said disorder is chosen fromsubstance abuse withdrawal syndromes.
 16. The combination according toclaim 2, wherein said antidepressant is a noradrenaline reuptakeinhibitor chosen from duloxetine, reboxetine, atomoxetine, desipramine,desvenlafaxine.
 17. The combination according to claim 2, wherein saidH3 antagonist/inverse agonist is chosen from one of the followingcompounds:

And any of their pharmaceutically acceptable salts, or solvates thereof.18. The combination according to claim 3, wherein said H3antagonist/inverse agonist is chosen from one of the followingcompounds:

And any of their pharmaceutically acceptable salts, or solvates thereof.19. The combination according to claim 2, wherein said H3antagonist/inverse agonist is the hydrochloride salt of


20. The combination according to claim 3, wherein said H3antagonist/inverse agonist is the hydrochloride salt of